Signal transduction in cells is defined as a biochemical communication from one part of the cell to another. Such communication between and within cells is carried out by, for example, binding of an extracellular ligand to a specific cell surface transmembranal receptor which are coupled to G-proteins in the cytoplasm or by regulation of ion channels such as Ca2+, Na+, K+, Cl−, or the like. Binding of the ligand to receptor induces a transmembranal signal which results in activation (or deactivation) of various cellular processes and functions. Small synthetic molecules that target these cellular receptors at the cell surface or intracellularly, with a high degree of specificity are highly desirable because of their rapid and increased tissue penetration, reduced immunogenicity and reduced metabolism when compared to monoclonal antibodies, their fragments or polypeptides.
The use of small molecules with gamma or positron emitting radiolabels also provides a means for non-invasive visualization and imaging of targeted receptors in both normal and diseased states. This has led to a search for small molecules labeled with positron emitting isotopes and single photon emitting isotopes that target various receptors and permit the non-invasive visualization of these receptors in the targeted tissues. See, for example, Nuclear Medicine Biology Vol 24, 485-498 1997. See also John (U.S. Pat. No. 5,919,934), Nuclear Medicine Biology vol 28, 657-666 2001, and PCT international publications of Mach (WO/0180905 A2 and WO 00/71171 A2).
Serotonin, also known as 5-hydroxytryptamine (5-HT), is an important neurotransmitter molecule and various receptor subtypes have been identified, among these receptor subtypes 5HT1A is one of the best characterized and studied as it is implicated in anxiety, depression, hallucinogenic behavior as well as in dementia such as Alzheimer's disease. See, for example, Neuropharmacology vol 38, 1083-1152 1999 and Euro.Journal of Nucl. Med. Vol 28, 113-129, 2001. A number of 99mTc-complexes with 2-methoxyphenylpiperazines have been investigated for binding and visualization of the 5HT1A receptor. See, also Nuclear Medicine Biology Vol 24, 485-498 1997; Technetium, rhenium and other metals in chemistry and nuclear medicine 5. Padova: Servizi Grafici Editoriali, 1999:393-9; and European Journal of Nuclear Medicine vol 29(2) 263-275, 2002.
In addition to its role as a neurotransmitter, 5HT can also function as a growth factor and is found in most neuroendocrine cells of the human prostate and in human prostate cancer cell lines. Several articles have reviewed 5HT's role in prostate cancer cell lines, for example, Anticancer Res 1987; 7:1-12; Cancer Res 1991; 51:2498-2505; and Cancer 1992; 70:254-68. A 5HT1A receptor antagonist has also been shown to inhibit prostate tumor cell growth in vivo (Anticancer Res 1994; 14:1215-20).
Sigma-receptors are recognized to be intra-cellular cytoplasmatic sites, distinguished in at least σ-1 and σ-2 subtypes (with a σ-3 site also postuated). Both subtypes are widely distributed in CNS (central nervous system), liver, kidney, lung, and in endocrine, immune, and reproductive tissues, and are overexpressed in several tumor cell lines (Vilner et al Cancer Res. 1995, 55, 408-413.). A recent review recites several potential applications for compounds having affinity for sigma receptors. Moreover, preliminary studies indicate that certain sigma agonists or sigma antagonists may be suitable for imaging or treating various cancers. See, for example, Wayne Bowen and Fabian Moebius (Pharm. Acta Helv. 2000, 74, 211-218; Trends Pharmacol. Sci. 1997, 18, 67-70.).
Similar to the serotonin receptors, the sigma receptors (including sigma-1 and sigma-2) that are normally expressed in the brain are also over expressed in a number of tumors. Sigma receptors, originally thought be a subclass of opiate receptors, are nondopaminergic, nonopiate membrane proteins that possess high affinity for haloperidol and various other neuroleptics. Two subtypes, termed σ-1 and σ-2 have now been identified.
The (+)-benzomorphans ((+)-[3H]-pentazocine) selectively label the σ-1 sites; the enantiomeric (−)-benzomorphans show lower affinity and no differentiation between the two sites. The σ-2 sites, however are identified with [3H]-DTG a nonselective s-1/s-2 ligand in the presence of dextrallophan, which masks binding of the 6-1 sites (Pharmacological reviews vol 42(4), 355-402, 1990).
Several studies have now been reported on the overexpression of sigma receptors in human and murine tumors including human melanoma, small cell lung carcinoma, human breast carcinomas and both androgen-dependent and -independent prostate carcinomas (Cancer Research vol 55(2), 408-413, 1995; Bioconjugate Chem 1997; 8:304-9; and Nucl Med Biol 1998; 25:189-94). See also John (U.S. Pat. No. 5,919,934), Nuclear medicine Biology vol 28, 657-666 2001, and international publications to Mach (WO/0180905 A2 and WO 00/71171 A2).
Adrenoreceptors, including α1 receptors, are another family of G-protein-coupled receptors expressed in the brain, and are expressed in prostatic diseases such as benign prostatic hyperplasia (BPH) and are used for the treatment of this disease (Journal of Andrology vol 12, 389-394, 1991 and Jour. Medicinal Chem. Vol 40, 1293-1315, 1997).
Malignant melanoma is one of the most highly invasive and metastatic tumors and causes 1 to 2 percent of all cancer deaths. Melanoma is an increasingly common malignancy as well, and its mortality rates have been rapidly increasing above those of any other cancer in recent years. Malignant melanoma ranks tenth in cancer incidence in 1998, and eighth in 2001 in the United States, there are 55,100 new cases for melanoma in the US 2004. As the early detection of the melanoma improves considerably the patient's prognosis, the search for in vivo diagnostic probes is of special interest.
2-[18F]Fluoro-2-deoxy-D-glucose ([18F]FDG) is widely used in positron emission tomographic (PET) imaging of various tumors including melanoma. Earlier attempts at imaging melanoma with radiolabeled peptides, such as 188Re- and 99mTc-labeled melanotropin, have generated encouraging results for in vivo melanoma scintigraphy.
The wide spread availability of 99mTc in most major hospitals and the routine use and practicality of SPECT imaging in nuclear medicine gives impetus to the development of such receptor-imaging agents labeled with technetium-99m. The use therapeutic rhenium-186 or rhenium-188 may permit the radiotherapy of diseases to which these small receptor-specific complexes bind.
The most widely used isotope in clinical nuclear medicine, technetium-99m, possesses ideal characteristics (t1/2=6.02 h, 140 keV monoenergeric γ-emission) for nuclear medicine imaging and is available on demand from a 99Mo-99mTc generator system.
Thus, new and useful radiolabeled diagnostic agents, including 99mTc and 186Re and 188Re labeled diagnostic agents, for imaging tissues, particularly tissues expressing or over expressing one or more of the receptors discussed supra, would be desirable. Moreover 99mTc and 186Re and 188Re labeled diagnostic and therapeutic agents suitable for use in imaging or treating melanoma, prostate cancer, other tumor or diseased states, various portions of the brain or other tissues expressing or overexpressing one or more receptors discussed supra would be desirable.